Influence of Type 2 Endoleaks on Long-Term Outcomes after Endovascular Repair for Abdominal Aortic Aneurysms: A National Hospital Organization Network Study for Abdominal Aortic Aneurysms in Japan.

BACKGROUND: Although endovascular repair (EVAR) is the first-line treatment for abdominal aortic aneurysm, type 2 endoleak (EL), which is associated with late sac enlargement or rupture, remains a concern. The present study aimed to assess the influence of type 2 EL on long-term outcomes after EVAR. METHODS: Among 550 patients who underwent EVAR between 2007 and 2013 at 14 Japanese national hospitals, 135 patients had type 2 EL diagnosed on follow-up computed tomography (CT) within 12 months after EVAR (EL2[+] group) and 415 patients did not have EL within 12 months (EL2[-] group). The cumulative incidences of sac enlargement, late intervention, and aneurysm-related death after EVAR were estimated using the cumulative incidence function method, and prognostic factors were investigated using the Fine-Gray hazard model. RESULTS: The median follow-up period was 5 years, and the 5-year cumulative incidence rates of sac enlargement, late intervention, and aneurysm-related death were 30.7% ± 4.4%, 25.3% ± 4.1%, and 2.6% ± 1.4%, respectively, in the EL2(+) group, and 8.7% ± 1.6%, 7.6% ± 1.4%, and 0.3% ± 0.3%, respectively, in the EL2(-) group. The cumulative incidence rates of sac enlargement (P = 0.002), late intervention (P < 0.001), and aneurysm-related death (P = 0.015) were significantly different between the 2 groups. As the first-line treatment for sac enlargement with type 2 EL, transcatheter coil embolization was performed in 30 patients. Information about sac behavior on CT after coil embolization was available in 20 of the 30 patients. Among these patients, no patients experienced sac shrinkage, and the aneurysmal sac dilated after coil embolization in 18 patients. CONCLUSIONS: Type 2 EL affects the long-term outcomes after EVAR. It is not recommended to observe large aneurysmal sacs conservatively as they tend to dilate in the presence of type 2 EL.

Late-Onset Malignant Neoplasms and Their Prognostic Factors after Abdominal Aortic Aneurysm Repair.

BACKGROUND: Little is known about late-onset primary malignant neoplasms after repair of abdominal aortic aneurysms (AAAs) despite malignancy being one of the primary causes of late death. We investigated the incidence and prognostic factors related to the occurrence of malignancy after AAA repair. METHODS: We performed a retrospective analysis of 589 patients who underwent AAA repair, including 264 endovascular AAA repairs and 325 open surgical repairs; 482 patients had no history of previous malignancy or concomitant malignancy, 72 had previous malignancy, and 35 had concomitant malignancy in remission at the time of AAA repair. The cumulative incidence rates of late-onset malignancy occurrence and cancer death were estimated using the cumulative incidence function in the presence of competing risks, that is, noncancer death, and prognostic factors were investigated using the Fine-Gray hazard model. RESULTS: After hospital discharge, 128 malignancies occurred in 116 patients. Overall cumulative incidence rates of late-onset malignancy occurrence at 1, 3, 5, and 10 years were 4.0%, 11.7%, 18.2%, and 38.1%, respectively. Multivariate analysis revealed that significant prognostic factors for late-onset malignancy included history of previous malignancy, current smoker, higher intraoperative blood loss, absence of allogeneic blood transfusion, lower C-reactive protein levels, and lower serum high-density lipoprotein-cholesterol levels. The type of surgical procedures for AAA repair did not affect the occurrence of malignancy. In addition, current smoker and higher intraoperative blood loss significantly increased the risk of cancer death. CONCLUSIONS: Current smoker and higher intraoperative blood loss were independent risk factors for late-onset malignancy after AAA repair. Late-onset malignancy after AAA repair should be monitored among patients at high risk and requires aggressive management to improve long-term survival.

Functional prognosis of critical limb ischemia and efficacy of restoration of direct flow below the ankle.

OBJECTIVE: Patients with critical limb ischemia have serious systemic comorbidities and are at high risk of impairment of limb function. In this study, we assessed the prognostic factors of limbs after revascularization. METHODS: In this retrospective single-center cohort study, from April 2008 to December 2012, we treated 154 limbs of 121 patients with critical limb ischemia by the endovascular therapy-first approach based on the patients' characteristics. The primary end point was amputation-free survival. Secondary end points were patency of a revascularized artery, major adverse limb events, or death. Furthermore, we investigated the ambulatory status one year after revascularization as prognosis of limb function. RESULTS: Endovascular therapy was performed in 85 limbs in 65 patients as the initial therapy (endovascular therapy group) and surgical reconstructive procedures (bypass group) were performed in 69 limbs in 56 patients. Early mortality within 30 days was not observed in either group. The primary patency rate was significantly better in the bypass group than in the endovascular therapy group ( p < 0.0001). Furthermore, the secondary patency rate was similar between the two groups ( p = 0.0096). There were no significant differences in amputation-free survival and major adverse limb event between the two groups. Univariate analysis showed that ulcer healing ( p < 0.0001), no hypoalbuminemia ( p = 0.0019), restoration of direct flow below the ankle ( p = 0.0219), no previous cerebrovascular disease ( p = 0.0389), and Rutherford 4 ( p = 0.0469) were predictive factors for preservation of ambulatory status one year after revascularization. In multivariate analysis, ulcer healing ( p < 0.0001) and restoration of direct flow below the ankle ( p = 0.0060) were significant predictors. CONCLUSIONS: Ulcer healing and restoration of direct flow below the ankle are independently associated with prognosis of limb functions in patients who undergo infrainguinal arterial reconstruction.

Prognostic factors of ulcer healing and amputation-free survival in patients with critical limb ischemia.

OBJECTIVE: A multidisciplinary approach is required to treat critical limb ischemia. We determined the poor prognostic factors of ischemic ulcer healing after optimal arterial revascularization, and assessed the efficacy of the medication therapy using cilostazol, which is a selective inhibitor of phosphodiesterase 3. METHODS: In this retrospective, single-center, cohort study, 129 limbs that underwent infrainguinal arterial revascularization for Rutherford class 5 critical limb ischemia were reviewed. The primary end point was the ulcer healing time after arterial revascularization. The secondary end point was the amputation-free survival rate. RESULTS: Of the 129 limbs, endovascular therapy was performed in 69 limbs, and surgical reconstructive procedures were performed in 60 limbs for initial therapy. Complete ulcer healing was achieved in 95 limbs (74%). The median ulcer healing time was 90 days. In multivariate analysis, no cilostazol use significantly inhibited ulcer healing ( p = 0.0114). A white blood cell count >10,000 ( p = 0.0185), a major defect after debridement ( p = 0.0215), and endovascular therapy ( p = 0.0308) were significant poor prognostic factors for ulcer healing. Additionally, ischemic heart disease ( p < 0.0001), albumin levels <3 g/dl ( p = 0.0016), no cilostazol use ( p = 0.0078), and a major defect after debridement ( p = 0.0208) were significant poor prognostic factors for amputation-free survival rate. CONCLUSIONS: Ulcer healing within 90 days after arterial revascularization is impaired by no cilostazol use, a white blood cell count >10,000, a major defect after debridement, and endovascular therapy. Furthermore, cilostazol improves amputation-free survival rate in patients with critical limb ischemia.

Early-phase wound healing and long-term outcomes of a selective endovascular-first approach for treating Rutherford 5 critical limb ischemia with infrainguinal lesions.

PURPOSE: To evaluate the validity of a selective endovascular-first approach for Rutherford 5 critical limb ischemia (CLI). METHODS: We analyzed, retrospectively, 51 limbs in 46 patients treated for Rutherford 5 CLI with infrainguinal lesions between 2010 and 2012. Endovascular therapy (EVT) and open surgical revascularization (OSR) were performed initially in 28 and 23 limbs, respectively. The interventions were assigned according to the systemic condition and femoropopiliteal TransAtlantic Inter-Society Consensus (TASC) II classification. We investigated early wound healing rates (defined as healing within 90 days) and amputation-free survival (AFS) rates in the EVT and OSR groups. RESULTS: The OSR group had more TASC D lesions (P < 0.0001). The early wound healing rate was significantly higher in the OSR group (OSR 46.1 % vs. EVT 14.3, P = 0.0205); however, the AFS rates did not differ significantly between the groups (P = 0.4031). Preoperative walking ability significantly influenced AFS (P < 0.0001). CONCLUSIONS: Our selective endovascular-first approach did not worsen AFS; however, OSR yielded better early wound healing rates. Preoperative walking ability strongly influenced AFS; hence, patients with good walking ability were good candidates for primary OSR. The indications for EVT for earlier wound healing still require better clarification.

Preoperative Cardiovascular Assessment and Late Cardiovascular Events after Elective Abdominal Aortic Aneurysm Repair.

BACKGROUND: Cardiovascular evaluation is performed before elective repair of abdominal aortic aneurysm (AAA) because of the high prevalence of cardiovascular disease. We investigated the association between preoperative cardiovascular evaluation and the incidence of late cardiovascular events after AAA repair. METHODS: We retrospectively analyzed 438 patients who underwent elective repair of AAA. Echocardiography, serial coronary assessment using functional myocardial scanning or coronary angiography, and carotid ultrasound scanning were performed preoperatively. Coronary revascularization after serial coronary assessment was performed preoperatively or simultaneously in 21 patients, and 54 patients had a remote history of coronary revascularization. RESULTS: The 5-year survival rate, incidence rate of cardiovascular events (myocardial infarction or stroke), and incidence rate of major adverse cardiovascular events (MACE; cardiovascular death or cardiovascular events) were 86.0%, 5.7%, and 11.5%, respectively. Carotid stenosis was associated with these long-term outcomes, and hypokinesis, determined by echocardiography, increased the incidence of cardiovascular events and MACE. Serial coronary assessment findings and history of previous or preoperative coronary revascularization were not associated with these long-term outcomes. CONCLUSIONS: Preoperative cardiovascular evaluation and treatment are beneficial for reducing not only perioperative risk but also late cardiovascular events.

Impact of introducing endovascular aneurysm repair on treatment strategy for repair of abdominal aortic aneurysm--National Hospital Organization network study in Japan.

BACKGROUND: The objective of the present study was to assess the hypothesis that the introduction of endovascular aneurysm repair (EVAR) into Japan has expanded the indication of abdominal aortic aneurysm (AAA) repair without increasing surgical mortality. METHODS AND RESULTS: From 10 national hospitals, we registered a total of 2,154 consecutive patients (Open surgery [OS]: n=1,577, EVAR: n=577) over 8 years, divided into 4 time periods: Group I (2005-2006: n=522), Group II (2007-2008: n=475), Group III (2009-2010: n=551), Group IV, (2011-2012: n=606). Mean age increased over the 4 time periods (P<0.0001). The incidences of COPD, smoking history, history of abdominal surgery and concomitant malignancy significantly increased as well, while the numbers of patients with preoperative shock or high ASA status reduced over time. The proportion of EVAR in AAA repair increased from: 0% in Group I, 11.6% in Group II, 41.0% in Group III, to 48.8% in Group IV (P<0.0001). Early mortality was 0.8% in the EVAR and 3.4% in the OS (P<0.001) groups. Survival rates among the 4 groups free of all-cause death and aneurysm-related death at 1 year were 92.1-96.3% (P=0.1555) and 95.5-96.8% (P=0.9891), respectively. Multiple logistic regression analysis for surgical death failed to demonstrate survival advantage of EVAR over OS. CONCLUSIONS: Introduction of EVAR expanded the indication of AAA repair without increasing mortality, while high risk for anesthesia and emergency cases reduced over time. UMIN-CTR (UMIN000008345).

DVC1-0101 to treat peripheral arterial disease: a Phase I/IIa open-label dose-escalation clinical trial.

We here report the results of a Phase I/IIa open-label four dose-escalation clinical study assessing the safety, tolerability, and possible therapeutic efficacy of a single intramuscular administration of DVC1-0101, a new gene transfer vector based on a nontransmissible recombinant Sendai virus (rSeV) expressing the human fibroblast growth factor-2 (FGF-2) gene (rSeV/dF-hFGF2), in patients with peripheral arterial disease (PAD). Gene transfer was done in 12 limbs of 12 patients with rest pain, and three of them had ischemic ulcer(s). No cardiovascular or other serious adverse events (SAEs) caused by gene transfer were detected in the patients over a 6-month follow-up. No infectious viral particles, as assessed by hemagglutination activity, were detected in any patient during the study. No representative elevation of proinflammatory cytokines or plasma FGF-2 was seen. Significant and continuous improvements in Rutherford category, absolute claudication distance (ACD), and rest pain were observed (P < 0.05 to 0.01). To the best of our knowledge, this is the first clinical trial of the use of a gene transfer vector based on rSeV. The single intramuscular administration of DVC1-0101 to PAD patients was safe and well tolerated, and resulted in significant improvements of limb function. Larger pivotal studies are warranted as a next step.

[Evaluation of anesthetic management and renal function in open and endovascular repair of abdominal aortic aneurysm].

BACKGROUND: Since 2007, the number of patients receiving endovascular aneurysm repairs (EVARs) is increasing in Japan. Although EVAR is less invasive and has a lower short-term mortality, it has no long-term advantages and may lead to deterioration of renal function. METHODS: We retrospectively evaluated anesthetic management and renal function in patients undergoing EVAR and open repair (OR) between July 2010 and June 2011. RESULTS: Sixty-three patients (EVAR 33, OR 30) were studied. The average age of patients was significantly older in the EVAR group, and the duration of surgery and anesthesia were longer in the OR group. Despite lower blood loss in the EVAR group compared with the OR group, a massive hemorrhage (1,563 g) occurred in the EVAR group. The renal function of the EVAR group did not deteriorate within 1 year after surgery. However, the rate of acute kidney injuries (AKI) was higher in patients with renal dysfunction before operation than in patients with normal renal function. CONCLUSIONS: Although EVAR is less invasive than OR, anesthesiologists should pay attention to pre-operative comorbidity and massive hemorrhage during the operation. To avoid postoperative renal dysfunction, it is important to protect the kidney during surgery.

Long-Term Outcomes of Endovascular Aneurysm Repair in Patients Aged ≤70 Years.

Objectives: The efficacy of endovascular aneurysm repair (EVAR) against abdominal aortic aneurysm (AAA) in younger patients remains unknown. Hence, the current study aimed to investigate whether the aneurysm-related mortality rate of EVAR is acceptable among patients aged ≤70 years. Methods: Among 644 patients, 148 underwent EVAR (EVAR group), and 496 received open surgical repair (OSR group). The cumulative incidence rates of aneurysm-related death, any intervention, and serious aneurysm-related events after AAA repair were evaluated using the cumulative incidence function in the presence of competing risks. Results: The EVAR group had higher prevalences of several comorbidities, and overall survival for the EVAR group was significantly inferior to that of the OSR group. The cumulative incidence rates of aneurysm-related death, any intervention, and serious aneurysm-related events at 5 years were 1.5%, 11.7%, and 6.4% in the EVAR group and 1.3%, 5.3%, and 5.9% in the OSR group, respectively. EVAR was not a significant prognostic factor of aneurysm-related mortality and serious aneurysm-related events. However, it was an independent poor prognostic factor of any intervention. Conclusion: EVAR was not a significant prognostic factor of aneurysm-related mortality and serious aneurysm-related events. Therefore, it demonstrated acceptable procedure-related long-term outcomes, at least in high-risk young patients.

A somatostatin analogue, octreotide, ameliorates intestinal ischemia-reperfusion injury through the early induction of heme oxygenase-1.

BACKGROUND: Intestinal damage after ischemia followed by revascularization, referred to as "ischemia-reperfusion (I/R) injury," is a devastating complication that can occur after acute superior mesenteric obstruction, or after both elective and emergent abdominal aortic surgery. Once an entire layer of intestine is involved in severe ischemia, the mortality rate reaches 90%; no effective medical treatment has been reported to date. Here, we demonstrate that a somatostatin analogue, octreotide, but not a free-radical scavenger, MCI-186, prevented death due to surgically induced intestinal I/R injury in rats. METHODS: Superior mesenteric artery (SMA) of Male Sprague-Dawley rats, that received MCI-186 or octreotide, was surgically clamped, and then the clips were removed and SMA blood flow restored. Survival was assessed, and blood and small intestine were subjected to cell count, enzyme-linked immunosorbent assay (ELISA), Western blotting, and immunohistochemistry. RESULTS: Of interest, pretreatment with octreotide, but not with MCI-186, just before induced intestinal ischemia prompted the early expression of heme oxygenase-1 (HO-1) protein-associated accumulation of CD68-positive cells, a possible cellular source of HO-1. Inversely, the administration of tin protoporphyrin IX (SnPPN), a specific inhibitor of HO-1, completely abolished the therapeutic effects of octreotide, indicating that the favorable effects of octreotide against intestinal I/R injury is predominantly dependent on the early induction of HO-1. CONCLUSIONS: These results suggest that a somatostatin analogue may be useful in leading to an improvement of the prognosis of patients with intestinal I/R injury in the clinical setting.

Gut dysbiosis and bacterial translocation in the aneurysmal wall and blood in patients with abdominal aortic aneurysm.

Inflammation plays a part in the development of abdominal aortic aneurysm (AAA), and the gut microbiota affects host inflammation by bacterial translocation. The relationship between abdominal aortic aneurysm and the gut microbiota remains unknown. This study aimed to detect bacterial translocation in the aneurysmal wall and blood of patients with abdominal aortic aneurysm, and to investigate the effect of the gut microbiota on abdominal aortic aneurysm. We investigated 30 patients with abdominal aortic aneurysm from 2017 to 2019. We analysed the aneurysmal wall and blood using highly sensitive reverse transcription-quantitative polymerase chain reaction, and the gut microbiota was investigated using next-generation sequencing. In the 30 patients, bacteria were detected by reverse transcription- quantitative polymerase chain reaction in 19 blood samples (detection rate, 63%) and in 11 aneurysmal wall samples (detection rate, 37%). In the gut microbiota analysis, the Firmicutes/Bacteroidetes ratio was increased. The neutrophil-lymphocyte ratio was higher (2.94 ± 1.77 vs 1.96 ± 0.61, P < 0.05) and the lymphocyte-monocyte ratio was lower (4.02 ± 1.25 vs 5.86 ± 1.38, P < 0.01) in the bacterial carrier group than in the bacterial non-carrier group in blood samples. The volume of intraluminal thrombus was significantly higher in the bacterial carrier group than in the bacterial non-carrier group in aneurysmal wall samples (64.0% vs 34.7%, P < 0.05). We confirmed gut dysbiosis and bacterial translocation to the blood and aneurysmal wall in patients with abdominal aortic aneurysm. There appears to be a relationship between the gut microbiota and abdominal aortic aneurysm.

Reduced proliferation of aged human vascular smooth muscle cells--role of oxygen-derived free radicals and BubR1 expression.

BACKGROUND: Aging is a risk factor for atherosclerosis. Recent studies suggest cell cycle events as well as reactive oxygen species (ROS) contribute to vascular cell dysfunction associated with aging. Mice expressing low levels of the spindle assembly checkpoint protein BubR1 develop aging-associated vascular changes at a young age, including decreased smooth muscle cells and increased reactive oxygen species (ROS) production. This study was designed to determine the effect of aging and production of oxygen-derived free radicals on expression of BubR1. MATERIALS AND METHODS: To assess cell proliferation capacity, human aortic smooth muscle cells (hAoSMC) derived from a young group (17-30 y) or an aged group (57-62 y) were cultured, and cell numbers were directly counted in using a Neubauer chamber. RT-PCR assay was used to evaluate BubR1 expression in cultured hAoSMC stimulated with Angiotensin II or H(2)O(2). RESULTS: No significant difference in BubR1 expression or hAoSMC proliferative ability was demonstrated at passage 5, but both were significantly decreased at passage 8 in the aged hAoSMC. Angiotensin II and H(2)O(2) up-regulated BubR1 expression in young hAoSMC, and the up-regulation was abrogated by a p38 MAPK inhibitor or an inhibitor of the NADH/NADPH oxidase. siRNA against BubR1 reduced proliferative activity and increased ROS production in hAoSMC. CONCLUSIONS: These findings demonstrate BubR1 mRNA expression decreases along with proliferation in aged hAoSMC. Aging-related loss of BubR1 and subsequent impairment of reactivity to ROS may explain reduced proliferative capacity of aged smooth muscle cells.

Increased Incidence of Cancer in Japanese Patients with Critical Limb Ischemia.

Objective: This multicenter observational study was conducted in order to investigate the incidence of cancer in patients with critical limb ischemia. Materials and Methods: We prospectively investigated the incidence of cancer in 68 patients with critical limb ischemia over a two-year period. Patients underwent an intensive examination at enrollment, which included tumor marker levels and chest and abdominal computed tomography, as well as one- and two-year follow-up examinations. We compared the observed incidence of cancer with the expected incidence calculated from national cancer rates by the standardized incidence ratio (SIR). Results: The majority (83.6%) of the patients were men, and 92.5% of the patients had a peripheral arterial disease that was classified as Fontaine stage III or IV. During enrollment, newly diagnosed cancers were detected in seven patients. Four additional cancers were detected during the follow-up period. All of the detected cancers were asymptomatic. We observed an increased risk of cancer (SIR, 4.04; 95% confidence interval, 1.31-9.42) in patients with critical limb ischemia. Conclusion: This study suggests that critical limb ischemia is associated with an increased risk of cancer. Our findings should be taken into serious consideration by future investigators considering the use of therapeutic angiogenesis.

Diabetic microangiopathy in ischemic limb is a disease of disturbance of the platelet-derived growth factor-BB/protein kinase C axis but not of impaired expression of angiogenic factors.

Diabetic foot is caused by microangiopathy and is suggested to be a result of impaired angiogenesis. Using a severe hindlimb ischemia model of streptozotocin-induced diabetic mice (STZ-DM), we show that diabetic foot is a disease solely of the disturbance of platelet-derived growth factor B-chain homodimer (PDGF-BB) expression but not responses of angiogenic factors. STZ-DM mice frequently lost their hindlimbs after induced ischemia, whereas non-DM mice did not. Screening of angiogenesis-related factors revealed that only the expression of PDGF-BB was impaired in the STZ-DM mice on baseline, as well as over a time course after limb ischemia. Supplementation of the PDGF-B gene resulted in the prevention of autoamputation, and, furthermore, a protein kinase C (PKC) inhibitor restored the PDGF-BB expression and also resulted in complete rescue of the limbs of the STZ-DM mice. Inhibition of overproduction of advanced-glycation end product resulted in dephosphorylation of PKC-alpha and restored expression of PDGF-BB irrespective of blood sugar and HbA1c, indicating that advanced-glycation end product is an essential regulator for PKC/PDGF-BB in diabetic state. These findings are clear evidence indicating that diabetic vascular complications are caused by impairment of the PKC/PDGF-B axis, but not by the impaired expression of angiogenic factors, and possibly imply the molecular target of diabetic foot.

Late Sac Behavior after Endovascular Aneurysm Repair for Abdominal Aortic Aneurysm.

BACKGROUND: Sac behavior after endovascular aneurysm repair (EVAR) for abdominal aortic aneurysms (AAAs) is considered as a surrogate for the risk of late rupture. The purpose of the study is to assess the sac behavior of AAAs after EVAR. METHODS AND RESULTS: Late sac enlargement (LSE) (≥5 mm) and late sac shrinkage (LSS) (≥5 mm) were analyzed in 589 consecutive patients who were registered at 14 national centers in Japan. The proportions of patients who had LSE at 1, 3 and 5 years were 2.6% ± 0.7%, 10.0% ± 1.6% and 19.0% ± 2.9%. The proportions of patients who had LSS at 1, 3 and 5 years were 50.1% ± 0.7%, 59.2% ± 2.3% and 61.7% ± 2.7%. Multiple logistic regression analysis identified two variables as a risk factor for LSE; persistent endoleak (Odds ratio 9.56 (4.84-19.49), P <0.001) and low platelet count (Odds ratio 0.92 (0.86-0.99), P = 0.0224). The leading cause of endoleak in patients with LSE was type II. CONCLUSIONS: The incidence of LSE is not negligible over 5 year period. Patients with persistent endoleak and/or low platelet count should carefully be observed for LSE. CLINICAL TRIAL REGISTRATION: UMIN-CTR (UMIN000008345).

Administration of a decoy against the activator protein-1 binding site suppresses neointimal thickening in rabbit balloon-injured arteries.

BACKGROUND: Transcription factor activator protein-1 (AP-1) is activated and upregulated in injured arterial smooth muscle cells in vivo, yet the exact role of the AP-1--related pathway in vascular disease in vivo has remained unclear. We examined the role of the transfer of synthetic double-stranded cis-element decoy oligodeoxynucleotides (ODNs) in balloon-injured rabbit carotid arteries and the effects of these ODNs on neointimal thickening. METHODS AND RESULTS: Transfection of fluorescein isothiocyanate--labeled ODNs using the hemagglutinating virus of Japan liposome method resulted in widespread distribution of fluorescent nuclear signals over the entire medial layer in injured arteries. Gel mobility shift assay revealed that AP-1 DNA binding was activated and that the AP-1 decoy reduced AP-1 DNA binding activity as a result of specific binding affinity to AP-1 in vivo. In morphometric analyses, AP-1 decoy led to a significant reduction in the neointimal area and a significant reduction in cell number and transforming growth factor-beta(1) production of human aortic smooth muscle cells under conditions of platelet-derived growth factor stimulation. CONCLUSIONS: Because AP-1 decoy transfection in vivo dramatically prevented neointimal thickening in balloon-injured arteries, AP-1 may be a useful molecular target for gene therapy to reduce restenosis.

Is Endovascular Aneurysm Repair a Relative Contraindication for Patients with Preoperative Renal Dysfunction?

UNLABELLED: Whether endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA) is a relative contraindication in patients with preoperative renal dysfunction (Pre-RD), remains controversial because the contrast medium may induce nephrotoxicity. In this study 1658 patients were treated at ten Japanese medical centers between January 2005 and March 2011 (Open surgery (OS) vs. EVAR: n = 1270 vs. n = 388). They were retrospectively analyzed. Multiple logistic regression analysis (MLRA) with pre- and intra-operative variables was applied to all patients. The endpoints induced onset of new dialysis and postoperative renal dysfunction (Post-RD), were defined as a 50% decrease or more from the preoperative estimated glomerular filtration rate (eGFR) level. RESULTS: Early mortality, Post-RD, incidence of new dialysis in all patients were 1.6% (OS: EVAR = 1.9%:0.8%), 6% (OS: EVAR = 8%:2.3%) and 1.4% (OS: EVAR = 1.5%:1.0%) respectively. MLRA identified operation time, clamp of renal artery as risk factors for Post-RD, and operation time and Pre-eGFR level as risk factors for new dialysis. CONCLUSION: Although Post-RD was more frequently observed in the OS group, MLRA showed that the choice of OS or EVAR was not a risk factor for Post-RD and new dialysis. It was strongly suggested that using contrast medium during EVAR is not a contraindication to AAA repair in patients with Pre-RD. (This article is a translation of J Jpn Coll Angiol 2014; 54: 13-18.).

Local blood serotonin and soluble P-selectin levels during percutaneous transluminal balloon angioplasty and primary stenting of the iliac artery.

BACKGROUND: The activation of platelets or leukocytes plays an important role in development of intimal hyperplasia. We investigated whether the local blood serotonin and soluble P-selectin levels changed during endovascular therapy of the iliac artery. METHODS: Blood samples were obtained from the iliac artery of 18 lower limbs undergoing percutaneous balloon angioplasty alone (8 limbs, group I) or percutaneous balloon angioplasty and primary stenting (10 limbs, group II). The serotonin levels in platelet-poor plasma were measured in all limbs. In group I the urinary level of the serotonin metabolite 5-hydroxyindoleacetic acid was also measured 24 hours before and 24 hours after the procedures. The soluble P-selectin levels were measured in the 6 patients in group II. RESULTS: Before angioplasty the mean (+/- SEM) serotonin concentrations were 1.2 +/- 0.2, 1.2 +/- 0.4, and 1.2 +/- 0.3 ng/mL in all cases, group I, and group II, respectively. After angioplasty these values changed to 1.7 +/- 0.4 (P =.0750), 1.2 +/- 0.4 (P =.8001), and 2.1 +/- 0.6 ng/mL (P =.0529), respectively. In group I urinary 5-hydroxyindoleacetic acid concentrations 24 hours before and 24 hours after the procedures were 0.0026 +/- 0.0004 and 0.0031 +/- 0.0006 mg/mg creatinine, respectively (P =.2566). In group II the soluble P-selectin levels significantly increased after intervention, from 26.0 +/- 5.7 to 33.9 +/- 5.3 ng/mL (P =.0296). CONCLUSIONS: Although the serotonin levels did not change significantly, the soluble P-selectin levels increased significantly after intervention. Leukocyte activation may therefore contribute to the progression of restenosis after peripheral endovascular therapy.

Intraluminal gene transfer of endothelial cell-nitric oxide synthase suppresses intimal hyperplasia of vein grafts in cholesterol-fed rabbit: a limited biological effect as a result of the loss of medial smooth muscle cells.

BACKGROUND: The intimal hyperplasia of vein grafts is a major cause of late graft failure and is more pronounced under hyperlipidemia. We previously reported that endothelial cell (ec)-type nitric oxide synthase (NOS) gene transfer inhibited graft intimal hyperplasia under poor runoff conditions. However, little information is available on either ecNOS gene transfer or intimal thickening under hypercholesterolemia. METHODS: Using the hemagglutinating virus of Japan liposomes, bovine ecNOS complentary DNA (5000 hemagglutinating activity units/mL) was transfected intraluminally to the right jugular vein, and these veins were then implanted as reversed vein grafts in an end-to-side fashion to the ipsilateral carotid artery. RESULTS: The cyclic guanosine 3',5'-monophosphate content of the ecNOS vein significantly increased in the grafts at 4 days after gene transfer, but the levels were only 25% greater than those found in the untreated veins. An immunohistochemical analysis at the same time suggested a large loss of medial smooth muscle cells that might have led to a reduction in the exogenous gene expression. The neointima of the ecNOS grafts was significantly reduced 4 weeks after implantation (P <.05), but the effect of ecNOS was limited to about a 30% inhibition. This reduction was associated with a reduced population of proliferating cells and decreased macrophage accumulation in the graft wall. CONCLUSIONS: These results demonstrated that the ecNOS gene transfer suppressed intimal hyperplasia of the vein grafts under hyperlipidemic conditions. However, this effect may be limited because of the smooth muscle cell loss related to the use of an intraluminal delivery methods. These data lead to speculation that the outcome of ecNOS gene transfer could be improved using different methods of gene delivery.